Stromal matrix metalloproteinase-9 regulates the vascular architecture in neuroblastoma by promoting pericyte recruitment
Stromal matrix metalloproteinase-9 regulates the vascular architecture in neuroblastoma by promoting pericyte recruitment
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DOI：
10.1158/0008-5472.can-03-0160
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发表时间：
2004-03-01
期刊：
影响因子：
11.2
通讯作者：
DeClerck, YA
中科院分区：
文献类型：
--
作者：
Chantrain, CF;Shimada, H;DeClerck, YA
晚期神经母细胞瘤显示基质金属蛋白酶MMP-2和MMP-9表达增加（Y。Sugiura等人，癌症研究所，58：2209-2216，1998），其已经涉及肿瘤进展的许多步骤，表明它们起促进作用。使用药理学和遗传学方法，我们研究了这些MMP在SK-N-BE进展中的作用（2）。10人神经母细胞瘤肿瘤原位异种移植到免疫缺陷小鼠中。用合成的MMPs抑制剂Prinomastat治疗的小鼠显示出抑制移植瘤中的肿瘤细胞增殖和延长生存期（50天比对照组的39天，P < 0.035）。普利诺司他治疗不影响肝转移瘤的形成（P = 0.52），但抑制了73.8%（P = 0.03）的肺内肿瘤细胞的血管内定植，并抑制了原发性肿瘤和实验性肝转移瘤的血管生成。来自普利诺司他处理的小鼠的原发性肿瘤显示通过肿瘤切片中的PECAM/CD 31染色检测到的内皮面积减少39.3%（P < 0.001），这主要是由于存在较小的血管（P = 0.004）。MMP-2由神经母细胞瘤肿瘤细胞和基质细胞表达，而MMP-9仅由基质细胞，特别是血管细胞表达。为了研究MMP-9对肿瘤血管生成的贡献，我们产生了RAG 1/MMP-9双缺陷小鼠。我们观察到在原位植入肿瘤细胞（P = 0.043）或皮下植入肿瘤细胞的免疫缺陷RAG 1/MMP-9双缺陷小鼠中血管生成的显著抑制。与肿瘤细胞和Matrigel的混合物相比（P < 0.001）。使用FITC标记的凝集素，我们证明了抑制MMP-9缺陷小鼠的肿瘤血管结构，导致更少和更小的血管。这些变化与沿着微血管存在的周细胞减少48%相关。总之，数据表明，在神经母细胞瘤中，基质来源的MMP-9通过促进血管形态发生和周细胞募集来促进血管生成。
Advanced stages of neuroblastoma show increased expression of matrix metalloproteinases MMP-2 and MMP-9 (Y. Sugiura et al., Cancer Res., 58: 2209-2216, 1998) that have been implicated in many steps of tumor progression, suggesting that they play a contributory role. Using pharmacological and genetic approaches, we have examined the role of these MMPs in progression of SK-N-BE (2).10 human neuroblastoma tumors orthotopically xenotransplanted into immunodeficient mice. Mice treated with Prinomastat, a synthetic inhibitor of MMPs, showed an inhibition of tumor cell proliferation in implanted tumors and a prolonged survival (50 versus 39 days in control group, P < 0.035). Treatment with Prinomastat did not affect formation of liver metastases (P = 0.52) but inhibited intravascular colonization by the tumor cells in the lung by 73.8% (P = 0.03) and angiogenesis in both primary tumors and experimental liver metastases. The primary tumors from Prinomastat-treated mice showed a 39.3% reduction in endothelial area detected by PECAM/CD31 staining in tumor sections (P < 0.001), primarily due to the presence of smaller vessels (P = 0.004). MMP-2 is expressed by neuroblastoma tumor cells and stromal cells, whereas MMP-9 is exclusively expressed by stromal cells, particularly vascular cells. To examine the contribution of MMP-9 to tumor angiogenesis, we generated RAG1/MMP-9 double-deficient mice. We observed a significant inhibition of angiogenesis in the immunodeficient RAG1/MMP-9 double-deficient mice orthotopically implanted with tumor cells (P = 0.043) or implanted s.c. with a mixture of tumor cells and Matrigel (P < 0.001). Using an FITC-labeled lectin, we demonstrated an inhibition in the architecture of the tumor vasculature in MMP-9-deficient mice, resulting in fewer and smaller blood vessels. These changes were associated with a 48% decrease in pericytes present along microvessels. Taken together, the data demonstrate that in neuroblastoma, stromally derived MMP-9 contributes to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment.